SNX-111, a novel, presynaptic N-type calcium channel antagonist, is neuroprotective against focal cerebral ischemia in rabbits.
Cytosolic Ca2+ overload has been proposed as a main cause of neuronal injury during cerebral ischemia. SNX-111, a synthetic product of the naturally occurring omega-conotoxin MVIIA, is a novel, presynaptic N-type Ca2+ channel antagonist and has been reported to be neuroprotective against cerebral ischemia. We studied the neuroprotective effects of SNX-111 in a rabbit model of focal cerebral ischemia. New Zealand white male rabbits (2.5-3.5 kg) were given 1 mg/kg/h i.v. SNX-111 (n=8) or normal saline (n=8) 10 min after onset of a 2-h period of transient focal cerebral ischemia induced by occlusion of the left middle cerebral, anterior cerebral and internal carotid arteries followed by 4 h reperfusion. SNX-111 significantly attenuated overall cortical ischemic neuronal damage by 44% (saline, 38.7+/-3.0%; SNX-111, 21.5+/-6.0%, P<0.05) and regions of hyperintensity on T2-weighted MRI by 30% (saline, 70.6+/-4.0%; SNX-111, 49.3+/-11.0%, P<0.05). No significant difference in (regional cerebral blood flow) rCBF or MAP (mean arterial blood pressure) was found between SNX-111- and saline-treated rabbits suggesting that neuroprotection is due to a cellular effect. We conclude that SNX-111 reduces ischemic injury in this model. Its use as a clinical neuroprotective agent for cerebrovascular surgery or stroke should be investigated further.
Perez-Pinzon
M A
MA
Department of Neurosurgery and Stanford Stroke Center, Stanford University Medical Center, CA 94305, USA.
Yenari
M A
MA
Sun
G H
GH
Kunis
D M
DM
Steinberg
G K
GK
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002545:Brain Ischemia / Q000473:pathology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D005073:Evoked Potentials, Somatosensory / Q000502:physiology; D008279:Magnetic Resonance Imaging; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D011817:Rabbits; D020960:omega-Conotoxins
D002121:Calcium Channel Blockers; D018696:Neuroprotective Agents; D010455:Peptides; D020960:omega-Conotoxins; C078452:ziconotide